Tacrolimus, also named FK506, is a macrolide pharmaceutical compound with the molecular formula C44H69NO12.H2O and molecular weight 882.05, having the chemical structural formula shown below:

Tacrolimus has expanded indications. It was initially used as graft rejection inhibitor for organ transplant patients. Later it was developed as ointment formulations for treating atopic dermatitis, and was further used as therapeutic agents for other inflammatory skin diseases. Currently, the dosage forms of tacrolimus are capsules, extended release capsules, ointment and so on.
The solubility of tacrolimus in water is extremely low and is only 1 to 2 μg/ml. When orally administered, tacrolimus in formulations can't be rapidly released, which leads to insufficient absorption rate in the body and thus causes lower drug bioavailability. In addition, there are significant variations between individuals after oral administration.
To solve these problems, various inventors have proposed different solutions, for example, Korean patent 10-0092145 disclosed dissolving tacrolimus in organic solvents, using hydroxypropyl methylcellulose as a dispersing carrier and preparing the mixture into a solid dispersion to improve its release rate; patent document WO95/01785 related to using nonionic surfactant polyglycerol fatty oils and sortitan anhydride fatty acid esters to improve its solubility; patent documents WO99/49863, EP1421939A1 and Korean patent 10-0440553 disclosed preparing sustained-release formulations (commercially available product) comprising: dissolving both the ethyl cellulose and tacrolimus in organic solvents, and then granulating the mixture with hydroxypropyl methylcellulose and lactose, drying the granules and milling the granules; patent document WO2012/053785A2 disclosed sustained-release pellets containing tacrolimus as the active ingredient. According to the patent specification, the sustained-release pellets consist of a five-layer structure including a core, a pharmacological active ingredient layer, a primary pharmacological inactive ingredient layer, a sustained-release layer, a secondary pharmacological inactive ingredient layer and an initial release membrane layer containing tacrolimus; patent document EP0240773B1 described a preparation method of immediate release capsules containing tacrolimus, which comprises dissolving tacrolimus in ethanol, adding hydroxypropyl methylcellulose as dispersing agent and dissolving the mixture in dichloromethane, preparing soft materials and drying, milling, sieving and filling; patent document CN1820759A described a preparation method of tacrolimus solid dispersion, wherein the active substance and carrier materials at mass ratios of 1:5-1:20 were prepared by the solvent method, the solvent-melting method or the freeze and drying method; patent document CN101098875A disclosed an amorphous tacrolimus and formulations containing amorphous tacrolimus comprising diluents, adhesives, disintegrants, glidants, lubricants, flavor correcting agent/flavor enhancing agent or colorants according to different usage.
The present inventors found that the formulations and preparation processes reported in EP0240773B1 and CN1820759A used dichloromethane. Dichloromethane is a Class II organic solvent and should be limited to use. The tacrolimus products prepared by the methods disclosed in other documents as discussed above have the problems of crystallization of tacrolimus in the dissolution medium or in vivo causing incomplete dissolution of tacrolimus and low drug plasma concentration and low drug efficacy.
To solve of the above problems, the present inventors eliminated organic solvent dichloromethane in preparation processes, which reduces the hazards to operators and environment and shortens operation procedures. Meanwhile, crystallization of tacrolimus in dissolution medium or in vivo can be avoided by regulating the amount of crystallization inhibitor used in the formulation, and thus avoiding low drug plasma concentration and low drug efficacy caused by the incomplete dissolution of tacrolimus. Also, the crystallization inhibitor can reduce the transformation of amorphous tacrolimus to crystalline form of tacrolimus in storage and can improve the stability of the drug.